CN111440142A

CN111440142A - Morpholinyl quinazoline compounds, processes for their preparation and intermediates therefor

Info

Publication number: CN111440142A
Application number: CN201911343427.0A
Authority: CN
Inventors: 许祖盛; 李纪志; 吴剑峰; 楼杨通
Original assignee: Shanghai Yingli Pharmaceutical Co Ltd
Current assignee: Shanghai Yingli Pharmaceutical Co Ltd
Priority date: 2019-01-16
Filing date: 2019-12-24
Publication date: 2020-07-24
Anticipated expiration: 2039-12-24
Also published as: US11505542B2; KR102405055B1; WO2020147525A1; CN111440142B; US20220127248A1; KR20210114999A; EP3912978A4; CA3126738A1; CA3126738C; JP2022508494A; EP3912978B1; EP3912978A1; JP7038263B2

Abstract

The invention discloses a preparation method and an intermediate of a morpholinyl quinazoline compound. The preparation method of the morpholinyl quinazoline compound provided by the invention comprises the following steps: step S1: carrying out the Suzuki reaction of the compound S and the compound IV as shown in the following formula to obtain a compound V; step S2: carrying out the following reaction on methylsulfonyl chloride and the compound V in an organic solvent to obtain a compound VI; step S3: and (3) carrying out coupling reaction on the compound VII and the compound VI in a solvent to obtain a compound YY-20394. The preparation method has the advantages of high yield, good selectivity, simple operation and mild reaction conditions, and is suitable for industrial production.

Description

Morpholinyl quinazoline compounds, processes for their preparation and intermediates therefor

Technical Field

The invention relates to a preparation method and an intermediate of a morpholinyl quinazoline compound.

Background

The morpholinyl quinazoline compound YY-20394 has a chemical structure of

Has effect in inhibiting phosphatidylinositol 3-kinase (PI 3K).

PI3K is an intracellular phosphoinositide kinase that catalyzes the phosphorylation of the hydroxyl group at position 3 of phosphatidylinositol PI3K can be divided into class I, class II and class III kinases, while the most widely studied class I PI3k mammalian cells, which are activated by cell surface receptors, are divided into class Ia and class Ib according to structure and receptor, which transmit signals from tyrosine kinase-coupled receptors and G protein-coupled receptors, class Ia PI3K includes PI3K α, PI3K β, PI3K subtypes, class Ib PI3K includes PI3K γ subtype (trends. biochem. sci.,1997,22, 267-pro 272), class Ia PI3K is a dimeric protein composed of catalytic subunit p110 and regulatory subunit p 4, with dual activity of kinases and protein kinases (nat. rev. cecr 2002,2, 9-pro) and inflammatory diseases related to cell proliferation and immune-associated diseases.

Patent WO2015055071A1 discloses a compound YY-20394 and a preparation method thereof. In the patent, 2-amino-5-fluorobenzoic acid is used as a raw material, a trichloro intermediate I-11 is synthesized through a 3-step reaction, and then a product YY-20394 is obtained through a four-step reaction conversion. The route is mainly suitable for the modification of a pharmaceutical chemical structure, but the reaction step of the compound I-11 to the compound I-11-a has poor selectivity and more generated impurities, and the yield of the compound I11-a is only 28 percent, so that the method is not beneficial to industrial production.

In view of this, it is urgently needed to develop a preparation method of the compound YY-20394, which has the advantages of high yield, good selectivity, capability of avoiding the generation of a byproduct at the 2-position on a quinazoline ring, simple operation, mild reaction conditions and suitability for industrial production.

Disclosure of Invention

The invention provides a preparation method and an intermediate of a morpholinyl quinazoline compound different from the prior art. The preparation method has the advantages of high yield, good selectivity, avoidance of generation of a byproduct at the 2-position of a quinazoline ring, improvement of the selectivity of a Suzuki reaction at the 4-position of the quinazoline ring, simple and convenient operation, mild reaction conditions and suitability for industrial production.

The invention is realized by the following technical scheme.

The invention provides a preparation method of a compound shown as a formula V, which comprises the following steps:

under the action of a palladium catalyst and an alkaline reagent, carrying out the Suzuki reaction of the following formula on a compound S and a compound IV in a solvent to obtain a compound V;

wherein R is¹And R²Independently is H or

(-Ms); m is

or-BF₃K；

X¹Is Cl or Br;

X²is halogen,

(-OTf) or

R³Is C_1-4An alkyl group;

R^4a、R^4b、R^4c、R^4dand R^4eIndependently H, C_1-6Alkyl, nitro or halogen.

R³In (A), the C_1-4The alkyl group is preferably a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a n-butyl group,

Or a tert-butyl group, more preferably a methyl group.

X²Among them, the halogen is preferably Cl, Br and I, and more preferably Cl.

R^4a、R^4b、R^4c、R^4dAnd R^4eWherein said halogen is independently preferably Cl, Br or I.

R^4a、R^4b、R^4c、R^4dAnd R^4eIn (A), the C_1-6Alkyl is independently preferably C_1-3The alkyl group is more preferably a methyl group, an ethyl group, an n-propyl group or an isopropyl group, and still more preferably a methyl group.

In one embodiment, M is

Preference is given to

In a certain embodiment, X is¹Is chlorine.

In a certain embodiment, X is²Is halogen,

Preference is given to

In a certain embodiment, R^4a、R^4b、R^4dAnd R^4eIndependently is H.

In a certain embodiment, R^4cPreferably nitro or C_1-6Alkyl, more preferably C_1-6An alkyl group.

In a certain embodiment, when X is²Is composed of

When is in use, the

Is composed of

(-OTs)。

The Suzuki reaction may be a reaction conventional in the art for such reactions.

In the Suzuki reaction, the palladium catalyst may be a palladium catalyst conventional in the art for such reactions, preferably tetrakis (triphenylphosphine) palladium (Pd (PPh)₃)₄) Palladium acetate Pd (OAc)₂Bis (triphenylphosphine) palladium dichloride (PdCl)₂(PPh₃)₂) Bis (tri-o-phenylphosphino) palladium (II) dichloride (PdCl)₂[P(o-tol)₃]₂) Tris (dibenzylideneacetone) dipalladium (Pd)₂(dba)₃) Bis (tri-tert-butylphosphine) palladium (Pd [ P (t-Bu) ]₃]₂) [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (PdCl)₂(dppf)) and [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride dichloromethane complex (PdCl)₂(dppf) DCM), more preferably tetrakis (triphenylphosphine) palladium.

In the Suzuki reaction, the palladium catalyst can also be reacted in the presence of a ligand. The ligand may be one conventional in the art for such reactions, preferably triphenylphosphine (PPh)₃) Tri-o-methylphenyl phosphorus (P (o-tol)₃) One or more of tri-tert-butylphosphine tetrafluoroborate, 2-dicyclohexylphosphine-2 ',4',6 '-triisopropylbiphenyl (x-Phos), 2-dicyclohexylphosphine-2', 6 '-dimethoxy-biphenyl (s-Phos) and 2-dicyclohexylphosphine-2', 6 '-diisopropoxy-1, 1' -biphenyl (Ru-Phos)And (4) a plurality of.

In the Suzuki reaction, the molar ratio of the palladium catalyst to the compound IV can be 0.01 to 0.5, preferably 0.02 to 0.2, for example 0.06.

In the Suzuki reaction, the solvent may be a solvent conventional in such reactions in the art, and is preferably a mixed solvent of an organic solvent and water. The organic solvent may be an organic solvent conventional in such reactions in the art, preferably one or more of aromatic hydrocarbon solvents, alcohol solvents, chlorinated hydrocarbon solvents and ether solvents, more preferably a mixed solvent of aromatic hydrocarbon solvents and alcohol solvents. The aromatic hydrocarbon solvent and the alcohol solvent are preferably toluene and isopropanol. The volume ratio of the aromatic hydrocarbon solvent to the alcohol solvent is preferably 1:1 to 5:1, more preferably 3:1 to 5:1, for example, 4: 1. The volume ratio of the organic solvent to the water may be a volume ratio conventional for such reactions in the art, preferably 1:1 to 10:1, more preferably 5:1 to 10: 1.

In the Suzuki reaction, the amount of the mixed solvent may not be specifically limited as long as the reaction is not affected.

In the Suzuki reaction, the basic agent may be one conventional in the art for such reactions, preferably one or more of alkali metal carbonates, alkali metal fluorides, alkali metal phosphates, alkali metal tert-butoxide, and alkali metal hydroxides. The alkali metal carbonate can be one or more of sodium carbonate, potassium carbonate and cesium carbonate, and potassium carbonate is preferred. The alkali metal fluoride salt may be potassium fluoride. The alkali metal phosphate may be potassium phosphate. The alkali metal tert-butoxide may be sodium tert-butoxide and/or potassium tert-butoxide. The alkali metal hydroxide may be one or more of sodium hydroxide, potassium hydroxide and lithium hydroxide.

In the Suzuki reaction, the molar ratio of the basic agent to the compound IV can be 1 to 10, such as 1.2, further such as 1.7, preferably 2 to 10, such as 9.

In the Suzuki reaction, the molar ratio of the compound S to the compound IV may be 0.9 to 3, preferably 0.9 to 1.5, such as 1.0, and also such as 1.2.

In the Suzuki reaction, the temperature of the Suzuki reaction may be a temperature that is conventional for such reactions in the art, preferably 0 to 130 ℃, more preferably 20 to 70 ℃, such as 45 ℃, and further such as 70 ℃.

The Suzuki reaction can be carried out under protective gas. The shielding gas may be a shielding gas conventional in the art for such reactions, such as nitrogen, and further such as argon.

The progress of the Suzuki reaction can be monitored by methods of monitoring such conventional in the art (e.g., T L C, again, e.g., L C-MS), typically with complete disappearance or no further reaction of the compound IV as the end point of the reaction, preferably for a period of 1 to 18 hours, e.g., 12 hours, again, e.g., 7 hours, again, e.g., 1 hour.

In the Suzuki reaction, the compound S is preferably

In the Suzuki reaction, the compound IV is preferably

After the Suzuki reaction is finished, the method also comprises the following post-treatment steps: cooling the reaction liquid after the reaction to room temperature, extracting, concentrating and carrying out column chromatography.

The preparation method of the compound shown in the formula V can also comprise a preparation method of the compound IV, which is a method 1 or a method 2:

the method comprises the following steps: which comprises the following steps: carrying out halogenation reaction on the compound III and the phosphorus trihalide and/or the phosphorus halide to obtain a compound IV;

the method 2 comprises the following steps: which comprises the following steps: carrying out nucleophilic substitution reaction of the compound III and a sulfonylation reagent in an organic solvent under the action of an alkaline reagent to obtain a compound IV;

the sulfonylation reagent is

Wherein R is³、R^4a、R^4b、R^4c、R^4d、R^4e、X¹And X²The definitions of (A) and (B) are the same as described above;

when X is present²When halogen is contained, the preparation method of the compound IV is the method 1;

when X is present²Is composed of

The preparation method of the compound IV is the method 2.

In method 1, the halogenation reaction may be a halogenation reaction conventional in the art for such a reaction.

In the method 1, the halogenation reaction is preferably carried out in the absence of a solvent (neat reaction).

In the method 1, the halogen in the "phosphorus trihalide and/or phosphorus halide" is a halogen, and the halogen is preferably Cl, Br or I, and more preferably Cl.

In the method 1, the molar ratio of the "phosphorus trihalide and/or phosphorus halide" to the compound III may be 1 or more, preferably 1 to 30, for example 20, and further for example 10.

In the method 1, the temperature of the halogenation reaction can be a temperature conventional in such reactions in the art, preferably 20 to 130 ℃, preferably 60 to 110 ℃, for example 105 ℃.

In method 1, the progress of the halogenation reaction can be monitored by such conventional monitoring methods in the art (e.g., T L C, e.g., L C-MS), and the end point of the reaction is generally defined as the complete disappearance of the compound III. the time of the halogenation reaction is preferably 2 to 24 hours, e.g., 3 hours.

In the method 1, after the halogenation reaction is finished, the following post-treatment steps can be further included: and quenching, extracting, washing and concentrating the reaction liquid after the halogenation reaction is finished.

In the method 1, in the post-treatment step, the reaction solution may be concentrated before the quenching.

In method 1, the said post-treatment step, the said quenching may be carried out in a manner conventional in the art for such reactions, preferably by adding water, more preferably by adding ice-water.

In method 1, the operation and conditions of the extraction in the post-treatment step may be those conventional in the art for such reactions. The extracted organic solvent may be a chlorinated hydrocarbon solvent, preferably dichloromethane.

In the method 1, in the post-treatment step, the water washing may be a conventional water washing in this type of reaction in the art, and preferably a water washing with saturated sodium chloride is used.

In the method 1, the operation and conditions of the concentration in the post-treatment step may be those conventional in the art for such reactions, such as concentration under reduced pressure.

In method 2, the alkaline agent may be an alkaline agent conventional in such reactions in the art, preferably an organic weak base and/or an inorganic weak base salt, more preferably an organic weak base. The organic weak base can be tertiary amine organic weak base and/or pyridine organic weak base. The tertiary amine organic weak base is preferably Triethylamine (TEA) and/or N, N-Diisopropylethylamine (DIPEA). The inorganic weak base salt may be an alkali metal carbonate, and potassium carbonate is further preferred.

In the process 2, when the sulfonylating agent is

When is in use, the

Preference is given to

In the process 2, when the sulfonylating agent is

When is in use, the

Preference is given to

In method 2, the molar ratio of the sulfonylating agent to the compound III may be a molar ratio customary in such reactions in the art, preferably 1 to 1.5, for example 1.

In method 2, the organic solvent may be an organic solvent conventional in such reactions in the art, preferably one or more of nitrile solvents, chlorinated hydrocarbon solvents and ether solvents. The nitrile solvent is preferably acetonitrile. The chlorinated hydrocarbon solvent is preferably dichloromethane and/or chloroform. The ether solvent is preferably one or more of tetrahydrofuran, 1, 4-dioxane and ethylene glycol dimethyl ether.

In the method 2, the amount of the organic solvent is not particularly limited as long as the reaction is not affected, and for example, the volume-to-mass ratio of the organic solvent to the compound III may be 5 to 15m L/g, for example, 10m L/g.

In method 2, the progress of the reaction can be monitored by methods conventional in the art for monitoring such reactions (e.g., T L C, also e.g., L C-MS), generally with complete disappearance of the compound III as the end point of the reaction, preferably for a period of 0.5 to 5 hours, e.g., 2 hours.

In the method 2, the temperature of the nucleophilic substitution reaction may be a conventional temperature for such a reaction in the art, and may be 0 to 130 ℃, or 50 to 100 ℃, for example, 70 ℃, or 80 ℃.

In the method 2, after the nucleophilic substitution reaction is finished, the following post-treatment steps can be further included: and cooling the reaction solution after the reaction to room temperature, adding water until solid is separated out, filtering and drying.

The compound III is preferably

The preparation method of the compound shown in the formula V can further comprise the following steps: in an organic solvent, carrying out nucleophilic substitution reaction of a compound II and a compound A as shown in the following formula to obtain a compound III;

the conditions for the nucleophilic substitution reaction may be those conventional in the art for such reactions.

In the nucleophilic substitution reaction, the organic solvent may be an organic solvent conventional in such reactions in the art, preferably a polar aprotic solvent. The polar aprotic solvent may be an amide-based solvent. The amide solvent may be N, N-Dimethylformamide (DMF) and/or N, N-Dimethylacetamide (DMAC), preferably N, N-dimethylacetamide.

In the nucleophilic substitution reaction, the amount of the organic solvent used is not particularly limited as long as the reaction is not affected, for example, the volume-to-mass ratio of the organic solvent to the compound II is 5 to 15m L/g, for example, 10m L/g.

In the nucleophilic substitution reaction, the molar ratio of the compound a to the compound II may be a conventional molar ratio in such reactions in the art, and may be 1 to 10, and may also be 1 to 3, for example, 2.4.

Wherein the temperature of the nucleophilic substitution reaction may be a temperature conventional in such reactions in the art, preferably 20 to 100 ℃, for example 85 ℃.

The progress of the nucleophilic substitution reaction can be monitored by methods conventionally used in the art (e.g., T L C, e.g., L C-MS), and the complete disappearance of the compound II is generally used as the end point of the reaction, and the time for the nucleophilic substitution reaction is preferably 1 to 24 hours, more preferably 1 to 5 hours, e.g., 2 hours.

Among them, the compound II is preferably

After the nucleophilic substitution reaction is finished, the following post-treatment steps can be further included: and (3) cooling the reaction liquid after the nucleophilic substitution reaction to room temperature, adding water until solid is separated out, filtering and drying.

The preparation method of the compound shown in the formula V can further comprise the following steps: under the action of an alkaline reagent, carrying out the following reaction of a compound I in a solvent to obtain a compound II,

the reaction conditions may be those conventional in such reactions in the art.

Among them, the solvent may be a solvent conventional in such reactions in the art, and a mixed solvent of an organic solvent and water is preferred. The organic solvent may be an organic solvent conventionally used in such reactions in the art, preferably one or more of a nitrile solvent, a ketone solvent, an ether solvent and an amide solvent, preferably a nitrile solvent. The nitrile solvent is preferably acetonitrile.

The amount of the solvent used is not particularly limited, as long as the reaction is not affected.

Wherein, the alkaline reagent can be the alkaline reagent conventional in the reaction in the field, and inorganic strong base is preferred. The inorganic strong base may be one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide and calcium hydroxide, preferably sodium hydroxide.

Wherein, the molar ratio of the alkaline reagent to the compound I can be the conventional molar ratio in the reaction in the field, and is preferably 1-20, such as 4.

Wherein the temperature of the reaction may be a temperature conventional in the art for such reactions, preferably 0 to 80 ℃, e.g. 45 ℃.

Wherein the progress of the substitution reaction can be monitored by methods conventional in the art (e.g. T L C, e.g. L C-MS), and the end point of the reaction is generally the complete disappearance of the compound I. the reaction time is preferably 8 to 18 hours, e.g. 12 hours.

After the reaction is finished, the method also comprises the following post-treatment steps: and cooling the reaction liquid after the reaction to room temperature, adjusting the pH value of the reaction liquid to 5-6, filtering and drying.

The invention also provides a preparation method of the compound shown as the formula YY-20394, which comprises the following steps:

step S1: under the action of a palladium catalyst and an alkaline reagent, carrying out a Suzuki reaction of the following formula on a compound S and a compound IV in a solvent to obtain a compound V;

step S2: under the action of an alkaline reagent, carrying out the following reaction on methylsulfonyl chloride and the compound V in an organic solvent to obtain a compound VI;

step S3: under the conditions of a palladium catalyst and a ligand and under the action of an alkaline reagent, carrying out a coupling reaction of a compound VII and a compound VI in a solvent as shown in the following formula to obtain a compound YY-20394;

wherein, X¹、X²、R¹And R²The definitions of (A) and (B) are the same as described above; when R in said compound V¹And R²At the same time are

The compound V is directly subjected to the coupling reaction of step S3 without step S2; the conditions and operation of the process for the preparation of the compound V are as described above.

In the preparation method of the compound shown as the formula YY-20394, when R in the compound V is¹And R²Is not H or at the same time

The compound V can be directly subjected to the coupling reaction of the step S3 without the step S2。

In step S2, the reaction conditions may be those conventional in such reactions in the art, and the following conditions are preferred in the present invention:

in step S2, the alkali agent is preferably a weak organic base. The weak organic base may be a weak organic base conventional in such reactions in the art. The organic weak base can be pyridine organic weak base and/or tertiary amine organic weak base, and pyridine organic weak base is preferred. The pyridine organic weak base can be pyridine.

In step S2, the molar ratio of the methanesulfonyl chloride to the compound V may be 1 to 5, for example, 2.

In step S2, the molar ratio of the alkaline reagent to the compound V may be 3 to 25, for example 23.

In step S2, the organic solvent is preferably a chlorinated hydrocarbon solvent. The halogenated hydrocarbon solvent is preferably dichloromethane.

In step S2, the reaction temperature may be 10-50 ℃.

In step S2, the progress of the reaction can be monitored by a monitoring method (such as T L C, e.g., L C-MS) which is conventional in the art, and the end point of the reaction is generally the complete disappearance of the compound V.

In step S2, the compound V is preferably

In step S2, after the reaction is completed, the method may further include the following post-treatment steps: quenching, filtering and pulping the reaction solution after the reaction is finished.

In step S3, the coupling reaction may be a coupling reaction conventional in the art.

In step S3, the palladium catalyst may be a palladium catalyst conventional in the art for such reactions, preferably tetrakis (triphenylphosphine) palladium (Pd (PPh)₃)₄) Palladium acetate Pd (OAc)₂Bis (triphenylphosphine) palladium dichloride (PdCl)₂(PPh₃)₂) Bis (tri-o-phenylphosphino) palladium (II) dichloride (PdCl)₂[P(o-tol)₃]₂) Tris (dibenzylideneacetone) dipalladium (Pd)₂(dba)₃) Bis (tri-tert-butylphosphine) palladium (Pd [ P (t-Bu) ]₃]₂) [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (PdCl)₂(dppf)) and [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride dichloromethane complex (PdCl)₂(dppf) DCM), more preferably palladium acetate.

In step S3, the molar ratio of the palladium catalyst to the compound VI may be 0.01 to 0.2, for example, 0.1.

In step S3, the ligand may be a ligand conventional in the art for such reactions, preferably triphenylphosphine (PPh)₃) Tri-o-methylphenyl phosphorus (P (o-tol)₃) One or more of tri-tert-butylphosphine tetrafluoroborate, 2-dicyclohexylphosphine-2 ',4',6' -triisopropylbiphenyl (x-Phos), 2-dicyclohexylphosphine-2 ',6' -dimethoxy-biphenyl (s-Phos) and 2-dicyclohexylphosphine-2 ',6' -diisopropoxy-1, 1' -biphenyl (Ru-Phos), preferably 2-dicyclohexylphosphine-2 ',4',6' -triisopropylbiphenyl.

In step S3, the molar ratio of the ligand to the compound VI may be 0.02-0.4, such as 0.2.

In step S3, the alkaline agent may be an alkaline agent conventional in such reactions in the art, preferably one or more of alkali metal carbonates, alkali metal fluorides, alkali metal phosphates, alkali metal tert-butoxide, and alkali metal hydroxides. The alkali metal carbonate can be one or more of sodium carbonate, potassium carbonate and cesium carbonate, preferably cesium carbonate (Cs)₂CO₃). The alkali metal fluoride salt may be potassium fluoride. The alkali metal phosphate may be potassium phosphate. The alkali metal salt of t-butanol may be sodium t-butoxide and/or potassium t-butoxide. The alkali metal hydroxide may be one or more of sodium hydroxide, potassium hydroxide and lithium hydroxide.

In step S3, the molar ratio of the basic agent to the compound VI may be 1 to 20, such as 3, such as 6, such as 10, such as 15, such as 20.

In step S3, the molar ratio of the compound VII to the compound VI may be 0.8 to 6, preferably 1 to 3, such as 5, and further such as 1.5.

In step S3, the solvent may be a solvent conventional in such reactions in the art, and is preferably a mixed solvent of a water-soluble organic solvent and water. The water-soluble organic solvent may be a water-soluble organic solvent which is conventional in such reactions in the art. The water-soluble organic solvent is preferably an ether solvent and/or an alcohol solvent, and more preferably an ether solvent. The ethereal solvent is preferably one or more of Tetrahydrofuran (THF), 1, 4-dioxane and ethylene glycol dimethyl ether, and more preferably tetrahydrofuran. The volume ratio of the organic solvent to water may be as conventional in the art, preferably 1:1 to 15:1, more preferably 3:1 to 15:1, such as 10:1, for example 4: 1.

In step S3, the coupling reaction may be performed in a manner conventional in the art, and may be performed in a conventional heating manner, or in a microwave condition.

When the coupling reaction is a conventional heating method, the temperature of the coupling reaction may be 30 to 130 ℃, preferably 80 to 120 ℃. The time of the coupling reaction can be 2-16 h, such as 12 h.

When the coupling reaction is a microwave reaction, the temperature of the coupling reaction can be 50-120 ℃. The time of the coupling reaction can be 5-16 h, such as 8h, and further such as 12 h.

In step S3, the compound VI is preferably

In step S3, the coupling reaction may also be carried out under a protective gas. The shielding gas may be a shielding gas conventional in the art, such as nitrogen, and further such as argon.

In step S3, after the coupling reaction is completed, the following post-treatment steps may be further included: and (3) extracting, washing, concentrating and carrying out chromatographic separation on the reaction solution after the reaction is finished.

The invention also provides a compound shown as the formula IV:

wherein, X¹And X²All as described above.

The compound IV is preferably

More preferably

The invention also provides a preparation method of the compound shown in the formula IV, which comprises the following steps of 1 or 2:

the method 2 comprises the following steps: which comprises the following steps: carrying out nucleophilic substitution reaction of the compound III and a sulfonylation reagent in an organic solvent under the action of an alkaline reagent to obtain a compound IV; the sulfonylation reagent is

when X is present²Is composed of

The preparation method of the compound IV is the method 2.

In the above reaction, the conditions of method 1 and method 2 are the same as those described above.

The invention also provides a compound III:

wherein, X¹Is Cl or Br.

The compound III is preferably

The invention also provides a preparation method of the compound III, which comprises the following steps: in an organic solvent, carrying out nucleophilic substitution reaction of a compound II and a compound A as shown in the following formula to obtain a compound III;

wherein, X¹Is Cl or Br.

Wherein, the conditions of the nucleophilic substitution reaction are the same as those described above.

The invention also provides a compound shown as the formula II:

the invention also provides a compound shown as the formula V-2:

wherein R is¹And R²Independently is H or

The compound V-2 is preferably

The above-mentioned preparation methods of the compounds may be combined as desired to obtain a synthetic route of the compound represented by the formula III, IV, V or YY-20394 (e.g., I → II → III → IV → V → VI → YY-20394, II → III → IV → V → VI → YY-20394, I → II → III → IV → V, I → II → III → IV, II → III → IV, I → II → III, etc.).

In the present invention, the following abbreviations are used:

tetrahydrofuran, t-Bu-t-butyl, DCM, dichloromethane, NCS, N-chlorosuccinimide, Ts, p-toluenesulfonyl, Ns, p-nitrotoluenesulfonyl, Ms, Tf, trifluoromethanesulfonyl, Ac, acetyl, DIPEA, diisopropylethylamine, DMF, N-dimethylformamide, DMAC, N-dimethylacetamide, DMSO, dimethyl sulfoxide, dba, dibenzylideneacetone, dppf, 1' -bis (diphenylphosphino) ferrocene, x-Phos 2-dicyclohexylphosphine-2 ',4',6' -triisopropylbiphenyl, s-Phos 2-dicyclohexylphosphine-2 ',6' -dimethoxy-biphenyl, Ru-Phos mass spectrometry 2-dicyclohexylphosphine-2 ',6' -diisopropoxyl-1, 1' -biphenyl, mg, 21mg, 85mg, electrospray, CMS, mass spectrometry, electrospray ionization, mass spectrometry, CMS, and electrospray ionization, mass spectrometry, or electrospray;¹h NMR ═ nuclear magnetic resonance; MHz-MHz; brs ═ broad singlet; d is doublet; t is a triplet; q is quartet; m is multiplet; dd ═ doublet; j is a coupling constant; n is moles per liter.

In the invention, the room temperature refers to the ambient temperature and is 10-35 ℃.

In the present invention, "overnight" means 8 to 16 hours.

In the present invention, "water-soluble organic solvent" means a solvent generally having a polar group in the molecule, for example, such as-OH, -SO₃H、-NH₂、-NHR、-COOH、-CN、-CO-、-CONH₂-a group and a carbon chain of 8 carbons or less. Acetone, acetonitrile and N, N-dimethylformamide are all common "water-soluble organic solvents".

The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.

The reagents and starting materials used in the present invention are commercially available.

The positive progress effects of the invention are as follows: the preparation method of the morpholinyl quinazoline compound improves the selectivity of the Suzuki reaction on the 4-position of the quinazoline ring, solves the problem of more byproducts in the reaction, has high yield, is simple and convenient to operate, has mild reaction conditions, and is suitable for industrial production.

Detailed Description

The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.

EXAMPLE 1 Synthesis of Compound I-11

2-amino-5-fluorobenzoic acid (100.2g, 0.65mol) was dissolved in DMF (600M L) and NCS (104.5g, 0.78mol) was added in portions with stirring at room temperature, after addition, water (1200M L) was added to the reaction solution with stirring overnight at room temperature to precipitate a solid, which was filtered, the cake was washed with water, dried, slurried with dichloromethane, filtered, and dried to give Compound I-11-1(85.1g, 70% yield) as an off-white solid L C-MS (ESI) where M/z was 190.0[ M + H ] (-)]⁺.

I-11-1(25.0g, 0.13mol) and urea (119.1g, 1.98mol) were added to a reaction flask, and the temperature was raised to 180 ℃ for reaction for 8 hours.The reaction was cooled to about 100 ℃, water was added and slurried for 2H, filtered, the filter cake was slurried twice more with water, filtered and dried to give compound I-11-2(26.7g, 94% yield) as a brown solid for direct use in the next reaction L C-ms (esi) M/z 215.0[ M + H ═ M]⁺.

Adding I-11-2(20.0g, 0.093mol) and phosphorus oxychloride (160g, 1.04mol) into a reaction bottle, dropwise adding DIPEA (24.0g, 0.19mol) at a temperature below 50 ℃, heating to 110 ℃, reacting for 2H, concentrating the reaction solution, adding toluene for 2 times, adding a small amount of toluene, slowly dropwise adding into water, controlling the temperature to be less than 40 ℃, continuously stirring for 0.5H, layering, extracting an aqueous layer with toluene, combining toluene phases, washing with saturated sodium chloride, drying with anhydrous magnesium sulfate, concentrating, pulping with n-heptane, filtering, and drying to obtain a compound I-11(19.9g, 85% yield) as a white-like solid, L C-MS (ESI), wherein M/z is 251.1[ M + H ], (ESI)]⁺.

EXAMPLE 2 Synthesis of Compound II-11

Sodium hydroxide solution (2N, 40M L) was added to a solution of compound I-11(5g, 0.020mol) in acetonitrile (70M L) at room temperature, after the addition, the reaction mixture was stirred at 45 ℃ overnight, the reaction mixture was cooled to room temperature, then hydrochloric acid solution (2N, 42M L) was slowly added in an ice-water bath to adjust the pH to 5-6, and a solid was precipitated, filtered, and the cake was washed with water and dried to give compound II-11(4.1g, 89% yield) as an off-white solid, L C-ms (esi) M/z 232.9[ M + H L ], (esi)]⁺；¹H NMR(400MHz,DMSO-d₆):13.63(brs,1H),8.06(dd,1H,J＝2.8,8.4Hz),7.78(dd,1H,J＝2.8,8.0Hz).

EXAMPLE 3 Synthesis of Compound III-11

Morpholine (2.7g, 0.031mol) was added to a solution of compound II-11(3g, 0.013mol) in DMAC (30m L) at room temperature, the reaction was stirred at 85 ℃ for 2h, the reaction was cooled to room temperatureWarm, water (70M L) was added under ice-water bath, solid precipitated, filtered, the filter cake washed with water and dried to give compound III-11(3.2g, 88% yield) as a pale yellow solid L C-ms (esi) M/z 284.1[ M + H ═]⁺；¹H NMR(400MHz,DMSO-d₆):11.69(brs,1H),7.81(dd,J＝8.4Hz,2.8Hz 1H),7.59(dd,J＝8.0Hz,2.8Hz 1H),3.55-3.80(m,8H).

EXAMPLE 4 Synthesis of Compound IV-11

To compound III-11(36.0g, 0.13mol) in acetonitrile (360M L), potassium carbonate (24g, 0.17mol) and p-toluenesulfonyl chloride (24.0g, 0.13mol) were added, respectively, at room temperature, followed by stirring at 80 ℃ for 2 hours, cooling the reaction mixture to room temperature, further dropwise adding water to the reaction mixture in an ice-water bath, controlling the temperature to be less than 25 ℃ until the dropwise addition was completed, continuing stirring for 1 hour, filtering, washing the filter cake with water, and drying to obtain compound IV-11(48g, 86% yield) as a yellow solid, L C-MS (ESI) where M/z is 438.0[ M + H ] 438.0]⁺.

EXAMPLE 5 Synthesis of Compound V-11

Compound IV-11(157.0g, 0.36mol), S-11(81.5g, 0.33mol), sodium carbonate (345.5g, 3.26mol), toluene (3.5L), isopropanol (1.2L), water (1.6L), nitrogen substitution three times, tetratriphenylphosphine palladium (18.8g, 0.016mol) was added under nitrogen protection, the reaction solution was stirred at 35-40 ℃ for 1h, the reaction solution was cooled to room temperature, the layers were separated, the aqueous phase was extracted with toluene, the toluene phase was combined, concentrated to a certain extent, n-heptane was added, filtration and silica gel column purification gave compound V-11(115g, 91% yield) as a yellow solid.¹H NMR(400MHz,CDCl₃):7.94(d,J＝2.8Hz,1H),7.63(dd,J＝8.0Hz,2.8Hz,1H),7.55(dd,J＝9.2Hz,2.8Hz,1H),7.24-7.27(m,1H),4.11(s，3H),3.90-4.06(m,6H),3.84(t,J＝5.2Hz,4H).

EXAMPLE 6 Synthesis of Compound VI-11

Under an ice salt bath, methanesulfonyl chloride (63.8g, 0.56mol) is added dropwise to a pyridine (550g, 6.59mol) solvent of the compound V-11(110g, 0.28mol), after the addition, the reaction solution is stirred at room temperature until the reaction is completed, water (1100M L) is carefully added to the reaction solution, the filtration is carried out, the filter cake is washed with water, the drying is carried out, the mixture is beaten with dichloromethane, the filtration and the drying are carried out, and the compound VI-11(105.0g, 80% yield) is obtained as a yellow solid, L C-MS (ESI) M/z is 468.1[ M + H ] 468.1]⁺；¹H NMR(400MHz,DMSO-d₆):9.53(s,1H),8.43(d,J＝2.4Hz,1H),8.07(dd,J＝11.2Hz,2.4Hz；1H),8.03(d,J＝2.4Hz,1H),7.57(dd,J＝9.2Hz,2.4Hz；1H),4.04(s,3H),3.92-3.86(m,4H),3.74-3.72(m,4H),.3.12(s,3H).

EXAMPLE 7 Synthesis of Compound VI-11

After methanesulfonyl chloride (1.24M L, 16.0mmol) was slowly added dropwise to a solution of compound S-11(2.0g, 8mmol) in pyridine (20M L) at 0-10 ℃, the reaction solution was stirred at room temperature overnight, pyridine was concentrated, saturated sodium bicarbonate (20M L) and dichloromethane (40M L) were added to the residue, the organic phase was separated, the aqueous phase was extracted with dichloromethane, the organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, and concentrated to give compound T-11(4.29g, 100% yield) as a yellow oil, L C-ms esi: (M/z: 329.2[ M + H) esi)]⁺.

To each reaction flask was added compound T-11[352mg, 0.65mmol (61% purity.)]IV-11(281mg, 0.64mmol), sodium carbonate (0.102g, 0.96mmol), tetrakistriphenylphosphine palladium (74mg, 0.064mmol), toluene/isopropanol/water mixture (volume ratio 4/1/1, 8m L), stirring at 60 deg.C for 4h, reacting, replacing with liquid nitrogen, concentrating, extracting the residue with dichloromethane, washing the organic phase with saturated sodium chloride, drying with anhydrous sodium sulfate, concentrating, pulping with dichloromethane, and filtering to obtain compound VI-11(170mg, 53% yield) as a yellow solid L C-ms (esi) M/z 468.1[ M + H ═]⁺.

EXAMPLE 8 Synthesis of Compounds VII-11

P-11(100g, 0.70mol), Q-21(127.5g, 0.63mol), acetonitrile (100g), potassium iodide (6g, 0.036mol) were added to the reaction flask, respectively. After the addition, the reaction mixture was stirred at 80 ℃ overnight. The reaction was concentrated, slurried with acetonitrile, filtered and dried to give compound VII-11(140.0g, 98%) as an off-white solid.¹H NMR(400MHz,D₂O):3.51(d,J＝12.8Hz,2H),2.80(t，J＝12.8Hz,2H),2.05-2.22(m,2H),1.90(d,J＝13.2Hz,2H),1.40-1.62(m,3H),1.12(s,6H).

EXAMPLE 9 Synthesis of YY-20394 Compound

Compound VI-11(35g, 0.075mol), compound VII-11(34g, 0.15mol), cesium carbonate (244g, 0.75 mol), x-Phos (3.55g, 0.0074mol), a mixture of THF and water (10/1v/v, 385M L), palladium acetate (0.84g, 0.0037mol) were added to the reaction flask, respectively, the mixture was replaced with nitrogen three times, stirred at 80 ℃ overnight, the reaction was cooled to room temperature, concentrated to remove THF, the residue was extracted with DCM, the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated, purified, slurried with ethanol, filtered, and dried to give compound YY-20394(26g, 59% yield) as a yellow solid, L C-ms (esi) as a silica gel column (M/z ═ 589.3[ M + H-ms: (esi): M/z: (589.3) [ M + H silica column (M)]⁺；¹H NMR(500MHz,DMSO-d₆)9.53(brs,1H),8.35(d,J＝2.0Hz,1H),8.01(d,J＝2.4Hz,1H),7.61(dd,J＝9.6Hz,2.4Hz,1H),7.39(dd,J＝9.6Hz,2.4Hz,1H),4.05(s,4H),3.87(s,2H),3.82-3.81(m,4H),3.73-3.72(m,4H),3.13(s,3H),2.94(d,J＝10.8Hz,1H),2.04-1.98(m,2H),1.66(d,J＝11.6Hz,2H),1.36-1.64(m,2H),1.21-1.18(m,1H),1.21-1.18(m,1H),1.04(s,6H).

EXAMPLE 10 Synthesis of Compound V-11

To a solution of compound III-11(1.0g, 3.52mmol) in acetonitrile (10m L) under ice-water bath was added dropwise methanesulfonyl chloride (0.55m L, 7.06mmol) and DIPEA (1.33m L, 7.76mmol) and after the end of addition, the mixture was stirred at room temperature for 2h, ice water (15m L) was added to the reaction and stirred for 10min, filtered, the filter cake was washed with water and dried to give compound IV-12(3.01g, 100%).

To a reaction flask were added compound IV-12(3.01g, 3.52mmol), compound S-11(0.88g, 3.52mmol), sodium carbonate (0.56g, 5.30mmol), palladium tetrakistriphenylphosphine (408mg, 0.353mmol), toluene/isopropanol/water mixture (volume ratio 4/1/1, 15M L), at room temperature, the reaction was replaced with nitrogen gas, the mixture was stirred at 30 ℃ for 2H, overnight at 45 ℃, the reaction solution was concentrated, methylene chloride (40M L) and water (20M L) were added to the residue, the methylene chloride phase was separated, the aqueous phase was extracted with methylene chloride, the organic phase was combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated, and purified to give compound V-11(1.02g, 74% yield) as a yellow solid, silica gel column, L C-ms esi (silica gel column): M/z ═ 390.2[ M + H: (M + H) and H11 (0.32 mmol), and the compound S-]⁺.

EXAMPLE 11 Synthesis of Compound V-11

To a solution of compound III-11(0.28g, 0.99mmol) in dichloromethane (10M L) was added DIPEA (0.26g, 2.0mmol) under ice-water bath, followed by dropwise addition of trifluoromethanesulfonic anhydride (0.56g, 2.0mmol), the mixture was stirred for 2H under ice-water bath, ice water (20M L) was added to the reaction solution, followed by extraction with dichloromethane (20 x 3M L), drying of the organic phase over anhydrous sodium sulfate and concentration to give compound IV-13(0.18g, 44% yield) as a brown solid L C-ms (esi): M/z 416.1[ M + H ═ 416.1]⁺.

To a reaction flask were added compound IV-13(0.18g, 0.43mmol), compound S11(0.2g, 0.8mmol), sodium carbonate (0.1g, 1.0mmol), tetratrixylite, respectively, at room temperaturePhenylphosphine palladium (33mg, 0.028mmol), toluene/isopropanol/water mixture (volume ratio 4/1/1, 6M L), after addition, the reaction solution was replaced with nitrogen, stirred at 70 ℃ for 6H, concentrated, added with ethyl acetate (8M L), filtered, the filtrate concentrated, and purified by preparative T L C (petroleum ether/ethyl acetate ═ 1/1) to give compound V-11(0.09g, 53% yield): L C-ms (esi): M/z ═ 390.1[ M + H ═ 1/1 ]]⁺.

EXAMPLE 12 Synthesis of Compound V-11

A mixture of compound III-11(1.0g, 3.52mmol) in phosphorus oxychloride (10m L) was stirred at 105 ℃ for 3h, the reaction was concentrated, toluene was taken twice, ice water (15m L) was added to the residue, and after stirring for 10min, extraction was carried out with dichloromethane, the organic phase was washed with saturated sodium chloride and concentrated to give compound IV-14(1.13g, 100% yield) as a yellow solid.

To a reaction flask were added at room temperature compound IV-14(1.13g, 3.52mmol), compound S-11(0.97g, 3.88mmol), sodium carbonate (0.66g, 6.23mmol), palladium tetrakistriphenylphosphine (408mg, 0.353mmol), toluene/isopropanol/water mixture (volume ratio 4/1/1, 60M L), after addition, the reaction liquid was replaced with nitrogen gas, stirred at 80 ℃ overnight, the reaction solution was concentrated, methylene chloride (50M L) and water (20M L) were added to the residue, the methylene chloride phase was separated, the aqueous phase was extracted with methylene chloride, the organic phase was combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, concentrated, and purified on silica gel to give compound V-11(1.21g, 88% yield) as a yellow solid, L C-MS (ESI) M/z ═ 390.2[ M + H ], [ ESI]⁺.

EXAMPLE 13 Synthesis of Compound VI-11

To a reaction flask, at room temperature, was added compound T-11(520mg, 0.97mmol) (61% pure as in example 7), potassium bifluoride (494mg, 6.34mmol), 1, 4-dioxane/water (10/1, 4m L by volume), and after the addition was completed, the mixture was stirred at room temperature for 1h, the reaction solution was filtered, the filter cake was washed with 1, 4-dioxane, the filtrates were combined, concentrated, and dried to give compound T-31(480mg, 100% yield) as a pale yellow oil.

Add Compound T-31(480mg, 0.97mmol), Compound IV-11(395mg, 0.90mmol), Cesium carbonate (340mg, 1.35mmol), Palladium acetate (10mg, 0.045mmol), X-Phos (43mg, 0.09mmol), THF/H to the reaction flask, respectively₂O (1/1, 8M L by volume), replacing the mixture with nitrogen, stirring at 60 ℃ for 2H, concentrating the reaction mixture, extracting the residue with dichloromethane, washing the organic phase with saturated sodium chloride, drying over anhydrous sodium sulfate, concentrating, slurrying with dichloromethane, filtering, and drying to give compound VI-11(280mg, 62% yield), L C-MS (ESI), M/z 468.1[ M + H ], (ESI)]⁺.

EXAMPLE 14 Synthesis of Compound V-11

Compound S-11(1.25g, 5.00mmol), sodium periodate (3.2g, 15.00mmol), ammonium acetate (1.1g, 15.00mmol) were added to a reaction flask, followed by addition of acetone (40M L) and water (10M L), heating to 80 ℃ and stirring for 12 hours, the reaction was terminated, the reaction mixture was concentrated, water (30M L) was added, and EA (50M L. sup.3) was used to extract the organic phase, whereby Compound S-21(0.66g, 78% yield) was obtained (L C-MS ESI) (M/z: 169.3[ M + H + ESI) ((M + H) yield)]⁺.

Compound IV-11(1.2g, 2.74mmol), S-21(0.51g, 3.04mmol), sodium carbonate (0.4g, 3.77mmol), toluene (16M L), isopropanol (4M L) and water (4M L) were charged into a reaction flask, stirred, replaced with nitrogen, tetratriphenylphosphine palladium (0.1g, 0.09mmol) was added into the reaction flask, replaced again with nitrogen, the temperature was raised to 60 ℃ to react for 12H, the reaction solution was concentrated, water (60M L) was added, filtered and dried to obtain crude product 0.76g, slurried with (petroleum ether/ethyl acetate 1/1) (40M L), and purified by column chromatography (petroleum ether/ethyl acetate 1/1) to obtain compound V-11(0.46g, 43%). L C-ms esi) (M/z ═ 390.1[ M + H ═ 1/1 ]]⁺.

EXAMPLE 15 Synthesis of Compound VI-11

To a solution of compound T-11(0.74g, 2.26mmol) in acetone (15m L) was added a solution of sodium periodate (1.45g, 6.78mmol) and ammonium acetate (0.87g, 11.3mmol) in water (5m L), the reaction was heated to 80 ℃ and reacted for 12 hours, the reaction was terminated, the solvent was concentrated to remove it, diluted hydrochloric acid (2N) was added, water was added, and the organic phase was extracted with ethyl acetate and concentrated to give compound T-21(0.54g, 96% yield).

Compound IV-11(0.5g, 1.14mmol), T-21(423mg, 1.72mmol), tetrakistriphenylphosphine palladium (132mg, 0.114mmol), sodium carbonate (363mg,3.42mmol), toluene (16M L), isopropanol (4M L) and water (4M L) were added to a reaction flask, the reaction solution was replaced with nitrogen, warmed to 60 ℃ overnight, spin-dried, added with water, extracted with ethyl acetate, the organic phase was washed with water, dried over anhydrous sodium sulfate, concentrated and the crude product was purified by column chromatography (DCM: MeOH ═ 50:1 to 20:1) to give compound VI-11(290mg, 54% yield), L C-ms (esi): M/z ═ 468.1[ M + H ═ 468.1[ (. M + H)]⁺.

EXAMPLE 16 Synthesis of YY-20394 Compound

Triethylamine (1.2g, 11.85mmol) was added to a solution of the compound S-11(1g, 4.00mmol) in dichloromethane (10m L), and MsCl (0.92g, 8.03mmol) was slowly added to the reaction solution in an ice-water bath, after the addition, the reaction solution was stirred at room temperature overnight, the reaction solution was concentrated to dryness, water was added, extraction was performed with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and concentrated to obtain a compound T-12(1.6g, 98% yield).

Adding the compounds IV-11(500mg, 1.14mmol), T-12(697mg, 1.72mmol), tetrakis (triphenylphosphine) palladium (132mg, 0.114mmol), sodium carbonate (363mg,3.42mmol), toluene (16m L), isopropanol (4m L) and water (4m L) into a reaction bottle respectively, replacing the reaction solution with nitrogen, heating to 60 ℃ for reaction overnight, concentrating the reaction solution to dryness, adding water, extracting with ethyl acetate, washing the organic phase with water, and adding anhydrous sulfuric acidSodium was dried, concentrated and the crude product purified by column chromatography (PE: EA ═ 1:1) to give compound VI-12(350mg, 56% yield). L C-ms (esi): M/z ═ 546.1[ M + H ═ 546.]⁺.

Add Compound VI-12(93mg, 0.17mmol), VII-11(192mg, 0.85mmol), Palladium acetate (4mg, 0.017mmol), x-phos (16mg, 0.034mmol), Cesium carbonate (166mg, 0.51mmol), THF (1.4M L) and Water (0.35M L) to a 10M L L microwave tube, replace the microwave tube with nitrogen, heat to 80 deg.C for overnight reaction, concentrate the reaction to dryness, add water, extract with ethyl acetate, wash the organic phase with water, dry over anhydrous sodium sulfate, concentrate, purify the crude by preparation T L C (DCM: MeOH ═ 30:1) to give Compound YY-20394(80mg, 80% yield) as a yellow solid L C-MS (ESI): M/z ═ 589.3[ M + H ], (ESI)]⁺.

EXAMPLE 17 Synthesis of Compound I-21

2-amino-5-fluorobenzoic acid (10g, 64.5mmol) was dissolved in DMF (50M L) and under stirring at room temperature NBS (12.6g, 70.9mmol) was added in portions, after which the reaction was stirred at room temperature overnight Water (120M L) was added to the reaction mixture and the solid precipitated, filtered, the filter cake washed with water and dried to give compound I-21-1(15g, 100%) as a yellow solid L C-MS (ESI) with M/z ═ 234.1[ M + H ] +.

Adding I-21-1(15g, 64.1mmol) and urea (38.5g, 641mmol) into a reaction flask, heating to 180 ℃ for reaction for 5H, cooling the reaction solution to about 100 ℃, adding water, pulping for 2H, filtering, pulping the filter cake twice with water, filtering, and drying to obtain compound I-21-2(16g, 96%) as a yellow solid, which is directly used for the next reaction, L C-MS (ESI) M/z 259.0[ M + H ],]⁺.

add I-21-2(16g, 61.8mmol) and phosphorus oxychloride (95g, 618mmol) to the flask and add DIPEA (16g, 123.6mmol) dropwise at room temperature. After the addition, the temperature is raised to 110 ℃ for reaction for 2 h. The reaction was concentrated, the concentrate was slowly poured into ice water, stirred for 10min, filtered, and the filter cake was dried to give compound I-21(19g, 100%).

EXAMPLE 18 Synthesis of Compounds II-21

Sodium hydroxide solution (2N, 128M L) was added to a solution of compound I-21(19g, 64.2mmol) in acetonitrile (240M L) at room temperature, the reaction mixture was stirred at 45 ℃ overnight, cooled to room temperature, and then hydrochloric acid solution (2N) was slowly added thereto in an ice water bath to adjust the pH to 5 to 6, and a solid was precipitated, filtered, and the cake was washed with water and dried to obtain compound II-21(10.3g, 58%). L C-ms (esi): M/z 277.]⁺.

EXAMPLE 19 Synthesis of Compounds III-21

To a solution of compound II-21(10.3g, 37.1mmol) in DMAC (60M L) at room temperature was added morpholine (8.1g, 92.8mmol) after addition, the reaction was stirred at 85 ℃ for 2H and the reaction cooled to room temperature, then water (70M L) was added under an ice water bath to precipitate a solid, filtered and the filter cake dried to give compound III-21(8g, 66%). L C-ms (esi) with M/z 328.1[ M + H89:]⁺.

EXAMPLE 20 Synthesis of Compounds IV-21

To compound III-21(0.5g, 1.52mmol) in acetonitrile (10M L) at room temperature were added potassium carbonate (274mg, 1.98mmol) and p-toluenesulfonyl chloride (290mg, 1.52mol), respectively, after the addition was completed, the reaction mixture was stirred at 80 ℃ for 2 hours, cooled to room temperature, and then dropwise added with water in an ice-water bath, while controlling the temperature to be lower than 25 ℃ and after the completion of the dropwise addition, the mixture was further stirred for 1 hour, filtered, and the filter cake was washed with water and dried to obtain compound IV-21(650mg, 88%) as a yellow solid, L C-MS (ESI) where M/z is 482.1[ M + H ], [ L]⁺.

EXAMPLE 21 Synthesis of Compound V-21

IV-21(200mg, 0.41mmol), compound S-11(104mg, 0.41mmol), tetrakis (triphenylphosphine) palladium (47mg, 0.041mmol), sodium carbonate (130mg, 1.23mmol), toluene (7.5M L), isopropanol (2.5M L) and water (3M L) were added to a reaction flask, the reaction solution was replaced with nitrogen, heated to 40 ℃ and stirred for 4 hours, water was added, ethyl acetate was extracted, the organic phase was washed with water, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by column chromatography (PE: EA: 3:1) to give compound V-21(140mg, 78%) as a yellow solid. L C-MS (ESI) M/z 434.1[ M + H ]]⁺.

EXAMPLE 22 Synthesis of Compound VI-21

To a solution of V-21(140mg, 0.32mmol) in pyridine (5M L) was added MsCl (37mg, 0.32mmol) under ice-bath conditions the reaction was stirred at room temperature overnight, spun dry, added water, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate and spun dry to give compound VI-21 as a yellow solid (160mg, 97%). L C-ms (esi): M/z 512.1[ M + H + esi ]: M/z]⁺.

EXAMPLE 23 Synthesis of YY-20394 Compound

Add Compound VI-21(140mg, 0.27mmol), Compound VII-11(308mg, 1.37mmol), Palladium acetate (6mg, 0.027mmol), x-phos (26mg, 0.054mmol), Cesium carbonate (264mg, 0.81mmol), THF (2M L) and Water (0.5M L) to a 10M L microwave tube, replace the microwave tube with nitrogen, warm to 80 deg.C overnight, spin dry the reaction, add water, extract with ethyl acetate, wash the organic phase with water, dry over anhydrous sodium sulfate, concentrate, purify the crude product by preparation T L C (DCM: MeOH ═ 30:1) to give YY-20394 as a yellow solid (80mg, 50%). L C-MS (ESI): M/z ═ 589.4[ M + H ], (ESI)]⁺.

EXAMPLE 24 Synthesis of Compound V-11

Adding the compound IV-11(159mg, 0.36mmol, 1equiv), the compound S-11(100mg, 0.40mmol, 1.1equiv), the sodium carbonate (385mg, 3.63mmol, 10equiv), the toluene (4.3m L), the isopropanol (1.5m L) and the water (2m L) into a reaction flask respectively, replacing three times by nitrogen, adding the tetrakis (triphenylphosphine) palladium (21mg, 0.018mmol, 0.05equiv) under the protection of nitrogen, stirring the reaction solution for 1h at 35-40 ℃, taking the reaction solution for L C-MS detection, detecting that the compound IV-11 in the reaction solution is completely converted, the content of the compound V-11 is 72.59% (wavelength 214nm), 99.03% (wavelength nm), after the reaction is finished, spin-drying the reaction solution, adding the water, extracting by ethyl acetate (25m 63), drying the organic phase, performing column chromatography (PE: 254 EA: 1.92% and purifying by yellow silica gel chromatography (yield: 6771.91-35 nm), and obtaining the purity of the compound IV-11 at 35-40 nm).

Comparative example 1

The Suzuki reaction was carried out under the conditions of example 24 by replacing the compound IV-11 of example 24 with the compound I-11(91mg, 0.36mmol, 1equiv), the reaction mixture was stirred at 35-40 ℃ for 1 hour, L C-MS detection was carried out on the reaction mixture, and it was detected that the content of the compound V-12 in the reaction mixture was 28.64% (wavelength 214nm), 35.39% (wavelength 254nm), and a large amount of the reactants I-11 and S-11 were present, the reaction mixture was further reacted at 35-40 ℃ and stirred overnight, L C-MS detection was carried out on the reaction mixture, and after detection, a part of the reactants I-11 and S-11 were present in the reaction mixture, the content of the compound V-12 was 35.28% (wavelength 214nm), 65.04% (wavelength 254nm), after the reaction was completed, the reaction mixture was spin-dried, water was added, ethyl acetate (25m spin-L) was used for extraction, the organic phase was obtained, and the yield (PE: EA column chromatography: 4:1) was found to yield, the compound V-12, the yield was 254 mg, 96% yellow solid purity was found to 3608% by 3608% wavelength 3608 (wavelength), and the wavelength was found to 3608 nm).

This comparative example compares the Suzuki reaction of Compound I-11 with Compound IV-11 under the same conditions, and the results are summarized in Table 1.

TABLE 1

Remarking: in table 1 "/" indicates that this was not done.

From the results in table 1, it is understood that the kind of the substituent at the 2-position of the quinoline ring affects the rate, progress, effect and yield of the Suzuki reaction under the same conditions. Compared with the substrate I-11 (namely the compound disclosed in the patent WO2015055071A1, wherein the 2-position of the quinoline ring is chlorine), the reaction time of the substrate IV-11 can be shortened to 1 hour, the yield is improved by 42 percent, the production efficiency is improved, and the production cost is reduced, which cannot be expected on the basis of the prior art. The inventor of the application, through continuous trial and screening, creatively discovers that the substrate IV-11 is subjected to Suzuki reaction, the reaction can obtain higher yield in a short time, and side reaction on the 2-position on a quinoline ring is avoided, so that the post-treatment is more favorable.

It is to be understood that the examples described herein are for illustrative purposes only and are intended to provide further understanding of the present invention, but are not intended to limit the scope of the present invention. Many modifications, both to materials and methods, may be made by one skilled in the art without departing from the scope of the invention, and such changes or modifications are intended to be included within the spirit and scope of this application and the scope of the appended claims.

Claims

1. A preparation method of a compound shown as a formula V is characterized by comprising the following steps:

wherein R is¹And R²Independently is H or

M is

or-BF₃K；X¹Is Cl or Br; x²Is halogen,

R³Is C_1-4An alkyl group; r^4a、R^4b、R^4c、R^4dAnd R^4eIndependently H, C_1-6Alkyl, nitro or halogen.

2. The method of claim 1, wherein X is²Wherein said halogen is Cl, Br and I, preferably Cl;

and/or, R³In (A), the C_1-4The alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl,

Or tert-butyl, preferably methyl;

and/or, R^4a、R^4b、R^4c、R^4dAnd R^4eWherein said halogen is independently Cl, Br or I;

and/or, R^4a、R^4b、R^4c、R^4dAnd R^4eIn (A), the C_1-6Alkyl is independently C_1-3The alkyl group is more preferably a methyl group, an ethyl group, an n-propyl group or an isopropyl group, and still more preferably a methyl group.

3. The method of claim 1, wherein M is

Preference is given to

And/or, X¹Is chlorine;

and/or, X²Is halogen,

Preference is given to

Further preferred is

And/or, R^4a、R^4b、R^4dAnd R^4eIndependently is H.

4. The method according to claim 1, wherein the palladium catalyst in the Suzuki reaction is tetrakis (triphenylphosphine) palladium, palladium acetate, bis (triphenylphosphine) palladium dichloride, bis (tris-o-methylphenylphosphine) palladium (II) dichloride, tris (dibenzylideneacetone) dipalladium, bis (tri-t-butylphosphine) palladium (Pd [ P (t-Bu)₃]₂) [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride and [1,1' -bis (diphenylphosphino) ferrocene]One or more of a palladium dichloride dichloromethane complex, preferably tetrakis (triphenylphosphine) palladium;

and/or, in the Suzuki reaction, when the palladium catalyst is reacted in the presence of a ligand; the ligand is one or more of triphenylphosphine, tri-o-phenylphosphine, tri-tert-butylphosphine tetrafluoroborate, 2-dicyclohexylphosphine-2 ',4',6 '-triisopropylbiphenyl, 2-dicyclohexylphosphine-2', 6 '-dimethoxy-biphenyl and 2-dicyclohexylphosphine-2', 6 '-diisopropoxy-1, 1' -biphenyl;

and/or in the Suzuki reaction, the molar ratio of the palladium catalyst to the compound IV is 0.01-0.5, preferably 0.02-0.2;

and/or in the Suzuki reaction, the solvent is a mixed solvent of an organic solvent and water; the organic solvent is one or more of aromatic hydrocarbon solvent, alcohol solvent, chlorohydrocarbon solvent and ether solvent, and preferably a mixed solvent of aromatic hydrocarbon solvent and alcohol solvent; the volume ratio of the organic solvent to the water is 1: 1-10: 1, preferably 5: 1-10: 1;

and/or, in the Suzuki reaction, the alkaline reagent is one or more of alkali metal carbonate, alkali metal fluoride salt, alkali metal phosphate, alkali metal tert-butoxide and alkali metal hydroxide;

and/or in the Suzuki reaction, the molar ratio of the alkaline reagent to the compound IV is 1-10, preferably 2-10;

and/or in the Suzuki reaction, the molar ratio of the compound S to the compound IV is 0.9-3, preferably 0.9-1.5;

and/or in the Suzuki reaction, the temperature of the Suzuki reaction is 0-130 ℃, and preferably 20-70 ℃;

and/or the Suzuki reaction is carried out under protective gas;

and/or in the Suzuki reaction, the compound S is

And/or in the Suzuki reaction, the compound IV is

5. The process according to any one of claims 1 to 4, which further comprises a process for producing the compound IV, which is process 1 or process 2:

the sulfonylation reagent is

when X is present²Is composed of

The preparation method of the compound IV is the method 2.

6. The process according to claim 5, wherein in Process 1, the halogenation is carried out in the absence of a solvent;

and/or, the halogen in the "phosphorus trihalide oxide and/or phosphorus halide" is halogen, and the halogen is Cl, Br or I, preferably Cl;

and/or, in the method 1, the molar ratio of the phosphorus trihalide and/or the phosphorus halide to the compound III is more than or equal to 1, preferably 1 to 30;

and/or in the method 1, the temperature of the halogenation reaction is 20-130 ℃, preferably 60-110 ℃;

and/or, in the method 2, the alkaline reagent is an organic weak base and/or an inorganic weak base salt, and the organic weak base is preferably a tertiary amine organic weak base and/or a pyridine organic weak base; the inorganic weak base salt is preferably an alkali metal carbonate;

and/or, in method 2, when the sulfonylating agent is

When is in use, the

Is composed of

And/or, in method 2, when the sulfonylating agent is

When is in use, the

Is composed of

And/or, in the method 2, the molar ratio of the sulfonylation reagent to the compound III is 1-1.5;

and/or, in the method 2, the organic solvent is one or more of a nitrile solvent, a chlorinated hydrocarbon solvent and an ether solvent;

and/or in the method 2, the volume-to-mass ratio of the organic solvent to the compound III is 5-15 m L/g.

7. The method of claim 5 or 6, further comprising the steps of: in an organic solvent, carrying out nucleophilic substitution reaction of a compound II and a compound A as shown in the following formula to obtain a compound III;

8. the method of claim 7, further comprising the steps of: under the action of an alkaline reagent, carrying out the following reaction of a compound I in a solvent to obtain a compound II;

9. a preparation method of a compound shown as a formula YY-20394 is characterized by comprising the following steps:

step S3: under the conditions of a palladium catalyst and a ligand and under the action of an alkaline reagent, carrying out coupling reaction of a compound VII and the compound VI in a solvent as shown in the following formula to obtain a compound YY-20394;

wherein, when R in the compound V¹And R²At the same time are

The compound V is directly subjected to the coupling reaction of step S3 without step S2;

in step S1, the conditions and operation of the process for producing Compound V are as defined in any one of claims 1 to 8.

10. The process of claim 9, wherein in the process for the preparation of the compound of formula YY-20394, when R is present in compound V¹And R²Is not H or at the same time

and/or, in step S2, the alkaline reagent is organic weak base; the organic weak base is preferably pyridine organic weak base and/or tertiary amine organic weak base, more preferably pyridine organic weak base, and even more preferably pyridine;

and/or in step S2, the molar ratio of the methylsulfonyl chloride to the compound V is 1-5;

and/or in step S2, the molar ratio of the alkaline reagent to the compound V is 3-25;

and/or, in step S2, the organic solvent is a chlorinated hydrocarbon solvent, more preferably dichloromethane;

and/or in the step S2, the reaction temperature is 10-50 ℃;

and/or, in step S2, the compound V is

And/or, in step S3, the palladium catalyst is tetrakis (triphenylphosphine) palladium, palladium acetate, bis (triphenylphosphine) palladium dichloride, bis (tri-o-tolylphosphine) palladium (II) dichloride, tris (dibenzylideneacetone) dipalladium, bis (tri-tert-butylphosphine) palladium (Pd [ P (t-Bu)₃]₂) [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride and [1,1' -bis (diphenylphosphino) ferrocene]One or more of a palladium dichloride dichloromethane complex, preferably palladium acetate;

and/or in step S3, the molar ratio of the palladium catalyst to the compound VI is 0.01-0.2;

and/or, in step S3, the ligand is one or more of triphenylphosphine, tri-o-methylphenyl phosphorus, tri-tert-butylphosphine tetrafluoroborate, 2-dicyclohexylphosphine-2 ',4',6' -triisopropylbiphenyl, 2-dicyclohexylphosphine-2 ',6' -dimethoxy-biphenyl and 2-dicyclohexylphosphine-2 ',6' -diisopropoxy-1, 1' -biphenyl, preferably 2-dicyclohexylphosphine-2 ',4',6' -triisopropylbiphenyl;

and/or in step S3, the molar ratio of the ligand to the compound VI is 0.02-0.4;

and/or, in step S3, the alkaline reagent is one or more of alkali metal carbonate, alkali metal fluoride, alkali metal phosphate, alkali metal tert-butoxide and alkali metal hydroxide;

and/or in step S3, the molar ratio of the alkaline reagent to the compound VI is 1-20;

and/or in step S3, the molar ratio of the compound VII to the compound VI is 0.8-6, preferably 1-3;

and/or, in step S3, the solvent is a mixed solvent of a water-soluble organic solvent and water; the organic solvent is a water-soluble organic solvent; the water-soluble organic solvent is preferably an ether solvent and/or an alcohol solvent, more preferably an ether solvent, even more preferably one or more of tetrahydrofuran, 1, 4-dioxane and ethylene glycol dimethyl ether, and even more preferably tetrahydrofuran; the volume ratio of the water-soluble organic solvent to water is 1: 1-15: 1, preferably 3: 1-15: 1;

and/or, in step S3, the compound VI is